According to WHO P. falciparum malaria is becoming increasing resistant to chloroquine, sulfadoxine-pyrimethamine and mefloquine (Eyles et al. 1963, Am. J. Torp. Med. Hyg. 12, 840-835; WHO Tech. Report Series No. 711, 1984; Boudreau et al. 1982 Lancet II, 1335; Noreen et al. 1991, Lancet 337, 1140-1143; Hurwitz et al. 1981, Lancet I, 1068-1070; Timmermanns et al 1982, Lancet I 11181).
Although quinine resistance is also emerging along Thailand-Myanmar border, still the quinine and tetracycline combinations remains over 80% effective in practice (Vanijanonta et al. 1992, Lancet 339,369). Besides, seven day regimen of quinine and tetracycline was found to be effective in treating P. falciparum cases which were resistant to artesunate, arteether and mefloquine combined therapy.
Mefloquine was reported to produce neuropsychiatric side-effects in adults who developed tonic clonic fits. Besides psychosis, delusions and hallucinations, anxiety sleep disturbances were also reported after mefloquine (Drugs 1990, 39, 160-169).
Multi-drug-resistance in P. falciparum malaria and high level of P. vivax resistant strains are posing a major threat to countries in South-east Asia. Africa and Southern America. Most seriously affected areas include Thai-Myanmar Burmese border, where resistance to nearly all available drugs (Chlorquine, sulfadoxine-pyrimethamine, mefloquine, quinine) has already got established, (WHO Report on Infectious Diseases, 1999, WHO/CDS/99.1).
Halofantrine is more effective but rather high doses of the drug are now required to control resistant P. falciparum Brasseur et al. 1993. Lancet 341, 901-2) which could lead to increased risk of cardiotoxicity of this new antimalarial including sinus bradycardia, sinus arrhythmia, tall peak T. waves, QT interval prolongation, ectopic beats (Karbwang et al. 1993, Lancet, 342, 501; Wildling et al. 1993. Lancet, 342, 55; Kremsner el al. Am. J. Trop. Med. Hyg. 50, 790-795) which has imposed great limitation on the antimalarial potential of this drug. Several reports have recently appeared which document emergence of chloroquine resistance by P. viva (Schwartz et al. 1991. New England J. Med. 324, 927; Schuurkamp et al. 1992. Trans. R. Soc. Trop. Med. Hyg. 86, 121-2; Murphy el al., 1993. Lancet, 341, 96-100; Garg et al. 1995. Trans. R. Soc. Trop. Med. Hyg. 89, 656-7; Than et al. 1995. Trans. R. Soc. Trop. Med. Hyg. 89, 307-8; Baird et al., 1996. Trans. R. Soc. Trop. Med. Hyg. 90, 409-410, Baird et al., Am. J. Trop. Med. Hyg. 56, 627-631. The World Health Organization (1984) had accorded high priority to the development of fast acting artemisinin derivatives as blood schizontocides for the emergency treatment of cerebral malaria as well as for the control of multiple drug resistant cases of Plasmodium falcipanum.
.alpha.,.beta.-arteether is an ethylether derivative of qinghaosu (artemisinine), which is extracted from Artemisia annua, a plant long known in traditional Chinese medicine for its antimalarial properties. .alpha.,.beta.-Arteether (30:70) (intramuscular) is one of the artemisinin derivatives that has been developed in India and shows antimalarial activity against chloroquine, mefloquine and quinine resistant P. yoelii nigeriensis and cures experimental cerebral malaria infections (P. knowlesi/P. fragile in rhesus monkey model). Dutta et al. 1989. Pharmacol. Res. 21, 415-19; Dutta and Tripathi, 1996, Japn. J. Trop. Med. Hyg. 24, 65-69; Tripathi et al. 1997, Exp. Parasitol. 87, 290-292; Bajpai et al. 1989 Trans. R. Soc. Trop. Med. Hyg. 83, 484).
.alpha.,.beta.-Arteether is relatively safer and its LD.sub.50 dose is 1250 mg/kg in Swiss mice as compared to artemether (LD.sub.50 263 mg/kg (im) and artesunate (LD.sub.50 475 mg/kg, im)(J. Trad. Chinese Med. 1982,2(1) 31-38). Clinical trials of intramuscular injection of this compound have been completed and marketed. Data on clinical trials with injectible preparation of .alpha.,.beta. arteether (30:70 mixtures of isomers amongst P.falciparum cases has been published (Mohapatra et al 1996. Indian J. Med. Res. 104, 284-7, Valecha et al. 1997, Int. J. Clin. Pharm. Res. XVII (1)11-15. Mohanty et al. 1997. Trans , R. Soc. Trop. Med. Hyg. 91, 328-330; Mishra et al. 1995, Trans. R. Soc. Trop. Med. Hyg. 89, 299-301).